PROJECT SUMMARY/ABSTRACT Vertebrates have evolved sophisticated immune systems to eliminate infections by helminth parasites (tapeworms, nematodes). Nevertheless, helminths often succeed in establishing persistent infections because they have evolved strategies to evade or manipulate their host's immune system. Because of this host-parasite co-evolution, infection success depends on an epistatic interaction between host immune genes and parasites' immune-evasion genes. But, the immunogenetic mechanisms underlying this epistasis remains poorly understood, because most studies focus on immunological effects of either host genes, or parasite genes, in isolation. Few experimental models of infection are amenable to `reciprocal mapping' ? the concurrent genetic analysis of both interacting species. A small fish, the threespine stickleback (Gasterosteus aculeatus), and its parasitic tapeworm (Schistocephalus solidus), offer an experimentally tractable system for reciprocal genetic analysis of trans-species epistasis between a vertebrate host and cestode parasite. Natural populations of stickleback have evolved different levels of resistance to S. solidus, presenting an opportunity to map genes underlying these hosts' rapid evolution of resistance (both cestode elimination and growth suppression) and parasite counter-adaptations. We have completed an initial quantitative trait locus (QTL) map of loci underlying host resistance to S. solidus. Our Aim 1 seeks to refine this map to pinpoint promising candidate genes, then experimentally test these genes' immunological effects via reciprocal hemizygosity tests. Because fish and human immune systems are similar, fish immune genes identified in Aim 1 may yield models of human resistance to helminths, and associated immune disorders (fibrosis, in particular). Several loci underlying stickleback immunity are effective only against certain parasite genotypes, demonstrating that trans-species epistasis is occurring. Aim 2 is to reciprocally map cestode genes that underlie variation in the parasites' response to host immunity. By combining QTL mapping, expression QTL mapping, and genome-wide association mapping (GWAS), we intend to identify a short-list of parasite candidate genes. Then, we will use reciprocal hemizygosity tests to experimentally test these parasite genes' effect on host gene expression, immune traits, and infection results, alone or epistatically with host loci. Finding parasite immunomodulation genes may reveal new approaches to treat helminth infections, or may reveal new therapeutic approaches to treat human auto-immune disorders. Aim 3 is to experimentally validate the protective functions of host phenotypes, by pharmacologically separating host genotype from host phenotype and testing for corresponding changes in cestode fitness. Ultimately, our goal is to identify host and parasite genes that jointly determine infection success, to understand (i) mechanisms of immunity to peritoneal helminth infections, (ii) how the cestode evolved to suppress or evade host immunity, and (iii) thereby learn how we might better treat helminth infections or associated immune pathology.